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BackgroundThe majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first year of life and succumb to disease if not lung transplanted. This register-based cohort study reviews patients with ABCA3 lung disease who survived beyond the age of 1 year.MethodOver a 21-year period, patients diagnosed as chILD due to ABCA3 deficiency were identified from the Kids Lung Register database. 44 patients survived beyond the first year of life and their long-term clinical course, oxygen supplementation and pulmonary function were reviewed. Chest CT and histopathology were scored blindly.ResultsAt the end of the observation period, median age was 6.3 years (IQR: 2.8–11.7) and 36/44 (82%) were still alive without transplantation. Patients who had never received supplemental oxygen therapy survived longer than those persistently required oxygen supplementation (9.7 (95% CI 6.7 to 27.7) vs 3.0 years (95% CI 1.5 to 5.0), p=0.0126). Interstitial lung disease was clearly progressive over time based on lung function (forced vital capacity % predicted absolute loss −1.1% /year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Lung histology pattern were variable (chronic pneumonitis of infancy, non-specific interstitial pneumonia, and desquamative interstitial pneumonia). In 37/44 subjects, theABCA3sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function.ConclusionThe natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course.

OA Förderung 2022 Background: Infections, major surgeries, and hyperinflammatory syndromes are known to trigger Systemic Inflammatory Response Syndrome (SIRS). Discrimination between infectious and noninfectious inflammation often poses a challenge in chronically ill patients with multiple comorbidities. These patients are routinely treated with a variety of anti-infective medications before a pathogen is iden- tified. With the goal of improving pathogen detection rates and interventions, we evaluated Next Generation Sequencing (NGS) as a highly sensitive and fast means of detecting free microbial DNA in a small amount of serum samples from children with ongoing SIRS. Methods: We describe seven complex pediatric patients of SIRS or prolonged fever (>38.5 °C) >72 hours in which serum samples ana- lyzed by NGS had a major impact on therapy. One patient was analyzed twice. Results: In eight NGS there were six positive results (two bacterial, three viral, one fungal) which were subsequently confirmed by microbiological culture or polymerase chain reaction (PCR) in five of the six NGS. In five of the eight performed NGS, results led to a change of therapy: antibiotic therapy was discontinued in two, escalated in one, an initiated in another; in one an antiviral was administered. Conclusions: NGS may become a valuable addition to infectious disease diagnostics in cases of pediatric SIRS. However, NGS has not yet been validated as a diagnostic method in pediatric as a diagnostic method in pediatric patients and results should therefore be interpreted with caution. Multi-center NGS evaluation studies are currently being planned.

Background: Sleep-disordered breathing (SDB) and disturbed sleep are common, often underrecognized, comorbidities in people with cystic fibrosis (pwCF). Objectives: We studied the effect of CFTR triple combination therapy elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on sleep in pwCF. Method: This was a prospective, observational sleep study in clinically stable adult pwCF. All participants underwent overnight polysomnography (PSG), before (T0) and after (T1) initiation of CFTR modulator therapy with ELX/TEZ/IVA. In addition, pulmonary function tests, calculation of BMI, and sweat chloride testing were performed. Results: Twenty-nine pwCF (mean age 32 ± 8 years; 15 female) participated in the study. Mean time between T0 and T1 was 194 ± 21 days. Total sleep time (TST) was 298 ± 40 min, with decreased sleep efficiency (SE) (76 ± 109) and increased sleep latency (SL) (73 ± 38 min). Sleep stages for NREM (N1–3) and REM sleep were within the normal range. Nocturnal respiratory events mainly occur during REM sleep (T0: AHI REM 8.3 ± 9.0/h; ODI REM 9.4 ± 10.6/h), whereas the overall AHI was normal (3.6 ± 3.7/h). After initiation of ELX/TEZ/IVA, we saw significant improvements in ppFEV1 (p < 0.001) and BMI (p < 0.001) and a reduction in sweat chloride levels (p < 0.001). In parallel, there was a reduction in AHI (p = 0.003), ODI (p = 0.001), and nocturnal respiratory rate (p < 0.001), both in total, REM and NREM sleep. Neither TST, SL, SE, nor sleep architecture was influenced (all p > 0.05). Conclusions: Initiation of ELX/TEZ/IVA resulted in significant improvements in SDB in adult pwCF.

BackgroundElexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation.MethodsWe conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV1 of 40–90% inclusive. After a 4-week run-in period, in which participants received tezacaftor 100 mg orally once daily and ivacaftor 150 mg orally every 12 h, participants were randomly assigned (1:1) to receive 24 weeks of either elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (elexacaftor plus tezacaftor plus ivacaftor group) or tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (tezacaftor plus ivacaftor group). Randomisation was stratified by percent predicted FEV1, age at screening visit, and whether the participant was receiving CFTR modulators at the time of the screening visit. Patients, investigators, and sponsor's study execution team were masked to treatment assignment. The primary endpoint was the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline (ie, at the end of the tezacaftor plus ivacaftor run-in period) up to and including week 24. The key secondary endpoint was the absolute change from baseline in percent predicted FEV1 up to and including week 24; other secondary endpoints were the absolute change from baseline in sweat chloride concentrations up to and including week 24, and safety and tolerability. All endpoints were assessed in all randomised patients who had received at least one dose of their assigned regimen. This study is registered with ClinicalTrials.gov, NCT04105972.FindingsBetween Oct 3, 2019, and July 24, 2020, 176 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 175 participants were randomly assigned (87 to the elexacaftor plus tezacaftor plus ivacaftor group and 88 to the tezacaftor plus ivacaftor group) and dosed in the treatment period. From baseline up to and including week 24, the mean CFQ-R respiratory domain score increased by 17·1 points (95% CI 14·1 to 20·1) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·2 points (−1·7 to 4·2) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 15·9 points [95% CI 11·7 to 20·1], pInterpretationThe elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population.

Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.

BACKGROUND: Home noninvasive ventilation (NIV) improves disease courses of patients with respiratory insufficiency due to neuromuscular diseases. Data about appropriate ventilator settings for pediatric patients are missing. METHODS: In this retrospective study, ventilator settings of 128 subjects with neuromuscular disease aged 0–17 y with NIV were compared between 4 age groups (< 1 y, 0–5 y, 6–11 y, and 12–17 y). Additionally, correlations of ventilator settings with age and vital capacity were investigated in an ungrouped approach. RESULTS: Ventilator backup rate decreased significantly with age, leading to significant backup rate differences between all groups except the oldest two. Median (interquartile range) backup rates were 36 (11.5), 24 (4), 20 (4), and 20 (3) breaths/min in groups 1–4, respectively. Median [IQR] expiratory positive airway pressures (4 [0.5], 4 [0], 4 [0], 4 [1] cm H(2)O, respectively) and median [IQR] inspiratory positive airway pressures (12 [1.5], 12 [5], 12 [2.3], and 14 [4] cm H(2)O, respectively) showed no significant differences. However, correlation analyses indicated an increase of inspiratory positive airway pressure with age and decreasing FVC, as well as an increase of backup rates with decreasing FVC. CONCLUSIONS: Similar NIV settings fit all age groups of pediatric subjects with neuromuscular disease. Thus, we propose an expiratory positive airway pressure of 4–5 cm H(2)O, an inspiratory pressure delta of 8–10 cm H(2)O, and an age-oriented backup rate as a starting point for NIV titration. Patients with advanced disease stages might require slightly higher inspiratory positive airway pressures and backup rates.

Introduction Hypersensitivity pneumonitis (HP) in children is a severe interstitial lung disease and potentially, a chronic condition, if not treated appropriately. No evidence-based guidelines are available; in particular, the role of systemic glucocorticoid therapy is unclear. Methods The aim of this randomized, double-blind, placebo-controlled, parallel-group, multi-center, phase II trial in pediatric HP was to assess the outcome of HP in children after 6 months of treatment and to compare 3 months of treatment with oral prednisolone or placebo. Results After 1.5 years and the inclusion of only four children, we terminated the study prematurely. Two of the children randomized to prednisolone did not achieve the predefined response of FVC to normal. One child treated with placebo recovered to normal, similar to another child treated with prednisolone. All children treated with steroids developed drug-related side effects. Discussion This uncompleted study illustrates the urgent medical need for evidence-based treatment protocols for this condition. We discuss the hurdles which were specific for completion of this trial in a rare condition. Among other options, we suggest the inclusion of children into an all-age study of HP, as in adults the same questions are unanswered.

Background. Regular physical activity plays an important role in the treatment of patients with cystic fibrosis (CF). This study is aimed at investigating the effects of a 12-month partially supervised exercise program on attributes of health-related and motor performance fitness, lung function (ppFEV1), BMI, and habitual physical activity (HPA, steps/day) in adults with CF. Methods. Attributes of health-related and motor performance fitness were examined at the beginning (T0), after 6 (T1), and 12 months (T2) on the basis of five test items: forward bend (FB), bent knee hip extension (HE), plank leg raise (PLR), standing long jump (SLJ), and standing on one leg (OLS). Additionally, we recorded HPA by accelerometry, peak exercise performance ( W peak ) by an incremental cycle test, ppFEV1, and BMI. During the first six months, there was close supervision by an experienced sport therapist. Results. 26 CF patients (8 female, mean age 26.5 ± 7.9 years; ppFEV1 53.7 ± 21.0 ) completed the exercise program. Significant improvements were recorded from T0 to T1 (FB: p ≤ 0.05 ; PLR, OLS: p ≤ 0.01 ) and from T0 to T2 (FB, PLR: p ≤ 0.01 and HE, OLS: p ≤ 0.05 ). W peak , ppFEV1, BMI, and HPA showed no significant improvement between the single test points and over the entire study period (all p > 0.05 ). Conclusion. Our results show trainability of adults with CF in aspects of health-related and motor performance fitness during a partially supervised exercise program. Close supervision positively influences the results. Using a simple test setup seems to be a promising tool for evaluating the effects of exercise programs in CF and could serve as an additional outcome parameter in future clinical trials. Trial registration: ClinicalTrials.gov (retrospectively registered May 8, 2018).

Introduction In pediatric patients, flexible bronchoscopy requires deep sedation. Different sedation regimes are common, but only some of them include opioids. Due to their antitussive effect, the use of short-acting opioids may be beneficial for this particular indication, but additional respiratory depression may lead to an increase in adverse events. Here, we systematically compared sedation regimes in children undergoing flexible bronchoscopy with either propofol alone, or a combination of propofol and remifentanil. The primary outcome parameter was the frequency of coughing episodes during the intervention. Secondary outcome parameters were frequency and types of complications, patient satisfaction, examiner satisfaction, and recovery time after finishing the sedation. Methods Fifty children aged 1-17 years undergoing flexible bronchoscopy under deep sedation with propofol were randomly assigned to two groups: PR receiving propofol and remifentanil and PP receiving propofol only. Sedation depth was predefined as Comfort Score 10-13. Results We found significantly less coughing episodes ([med (IQR)] PR: 0.73 (0.28-2.45)/min; PP: 1.98 (1.26-3.12)/min; p = .010) and shorter recovery time in Group PR (PR: 13.5 (8-17.5) min; PP: 21.0 (14-27) min; p = .011). Examiner's satisfaction was higher in Group PR (PR: 10 (8-10); PP: 9 (7-9); p = .012). The number of adverse events, patient satisfaction, and required propofol dose during the intervention did not differ between groups. Conclusion We suggest the combination of propofol with remifentanil instead of using propofol alone in pediatric procedural sedation for flexible bronchoscopy.

Objective To examine the effect of intrathecal application of nusinersen on the respiratory function in terms of vital capacity in pediatric patients with spinal muscular atrophy (SMA). SMA is characterized by on-going muscular atrophy and weakness that lead to respiratory insufficiency. In recent years therapy with nusinersen has been shown to improve motor function in patients with SMA. Methods We retrospectively analyzed data from 12 pediatric patients (aged 4–12 years) with SMA II or III (7 walkers, 5 sitters) treated with nusinersen. We examined forced vital capacity (FVC) at baseline (i.e., before treatment) and 180 and 300 days after initiation of treatment. Results No significant difference in the ranks of FVC of patients with SMA at baseline and day 300 was found and, thus, stable FVCs are implied (n = 6; Z = - 0.105, pexact = 1.000; Medianbaseline = 96.0%, 95%-CI [86.5, 110.5]; Medianday300 = 96.0%, 95%-CI [92.0, 109.5]; s. Table 1). This also applied to the comparison between baseline and day 180 (n = 7; Z = 0.00, pexact = 1.00; Medianbaseline = 93.0%, 95%-CI [85.0, 110.0]; Medianday180 = 91.0%, 95%-CI [72.0, 118.0]) and day 180 and 300 (n = 9; Z = - 0.533, pexact = .652; Medianday180 = 95.0%, 95%-CI [72.0, 118.0]; Medianday300 = 90.0%, 95%-CI [74.0, 105.0]). Conclusion Nusinersen therapy alone may not improve lung function of pediatric patients with SMA type II or III.

Background: Diagnosis and treatment of paediatric tuberculosis resistant to both isoniazid and rifampicin (MDR-pTB) remain challenging due to paucibacillary disease, low sensitivity and specificity of diagnostic tools and frequently changing guidelines Aims and objective: This study aimed to describe epidemiology, clinical characteristics and outcome of MDR-TB among children and adolescents in Germany. Methods: We collected all cases of MDR-pTB registered in Germany from 2010 to 2020 and compared their data to an adequate control sample with drug-sensitive TB. Results: 52 subjects with MDR-pTB (24 active MDR-TB, 28 MDR-LTBI) and 56 controls were included. The annual incidence of MDR-TB rose from two in 2010 to nine in 2020. Time to diagnosis was longer in MDR-pTB compared to drug-sensitive TB (43 vs. 8 days, p Conclusions: Early diagnosis, identification of potential MDR index, appropriate treatment and follow-up are essential in MDR-pTB. Therefore, better cooperation between clinics and public health care is required in Germany. In children with an MDR-TB index case or in those born in a MDR high-incidence country, bacteriological confirmation including PCR-based susceptibility testing should always be initiated. The individual drug regimen has to be adapted to the patients’ or index’ susceptibility testing results.

BACKGROUND: Sleep disturbances and poor sleep quality are a known phenomenon in patients with Cystic Fibrosis (CF). Habitual physical activity (HPA) plays an important role in the treatment of CF patients due to its positive influence on progression of disease and quality of life. The aim of this work is to create a home-based sleep and activity profile and to investigate the influence of habitual physical activity (HPA) on sleep quality of children, adolescents and adults with CF. METHODS: One hundred and nine CF patients (64 male, mean age 22.7±12.0 years; mean ppFEV1 63.0±26.7) were equipped with an actigraph (Actigraph Corp., Pensacola, FL, United States) for home-based collection of activity and sleep data for a total of 4 weeks. Evaluation of recorded raw data was performed by ActiLife software, Version 6.11.9 (Actigraph Corp., Pensacola, FL, United States). RESULTS: CF patients under the age of 18 show the best sleep efficiency (92%±3%), the longest time in bed (TIB) (545±71 min) and Total Sleep Time (504±72 min) and the lowest Wake after sleep Onset (WASO) (39±15 min). With increasing age there is a decrease in Sleep efficiency (SE) (P0.05). In terms of lung function, CF patients with FEV1 values > 70%pred. have the best SE (92%±3%), the highest TST (490±72 min) and TIB (531±71 min) and the lowest WASO (39±13 min). As FEV1 deteriorates, a change in sleeping behavior can be detected. SE (P0.05) decrease, whereas WASO (P>0.05) increases. Interestingly, there is no difference in the number of awakenings between the different age and FEV1 groups (all P>0.05). Statistical analysis was performed using version 25 of the SPSS statistics package (SPSS Inc., Chicago, USA). CONCLUSIONS: Besides younger age and higher FEV1, daily activity in higher intensities influences sleep of CF patients in a positive way. Patients with poor quality and disturbances of sleep possibly benefit from an intensification of physical activity in the home environment.

Pompe disease is a rare metabolic myopathy caused by deficiency of lysosomal α-glucosidase. Reduced enzyme activity results in abnormal intra- and extralysosomal glycogen deposition as well as impaired cellular function and autophagy. Age at manifestation and severity of disease depend on residual enzyme activity. Enzyme replacement therapy (ERT) is available since 2006. In infantile onset Pompe disease, the most severe form, markedly prolonged survival has resulted in a new phenotype with symptoms and problems not encountered previously. In addition, it became apparent that antibody formation against the recombinant human enzyme may adversely affect the response to ERT. This review summarizes new knowledge gained in the last years concerning care of pediatric patients with Pompe disease and gives recommendations for diagnostics, treatment, and follow-up.Morbus Pompe ist eine seltene metabolische Myopathie, bei der ein Mangel an lysosomaler Alpha-Glukosidase zur pathologischen intra- und extralysosomalen Speicherung von Glykogen sowie zu gestörter Autophagie führt. Je nach Alter bei Beginn können klassisch infantile sowie kindliche, juvenile und adulte Formen unterschieden werden. Alter bei Manifestation und Schweregrad hängen von der Enzym-Restaktivität ab. Seit 2006 ist eine Enzymersatztherapie (EET) verfügbar. Das verlängerte Überleben von Patienten mit infantiler Verlaufsform führt zum Auftreten neuer Symptome, die bisher bei diesen Kindern nicht beschrieben wurden. Zudem hat sich gezeigt, dass eine Antikörperbildung gegen das rekombinante humane Enzym den Erfolg der EET negativ beeinflussen kann. Dieser Artikel fasst neue Erkenntnisse zusammen, die in den letzten Jahren hinsichtlich neuer klinischer Symptome und therapeutischer Probleme gewonnen wurden, und gibt Empfehlungen für Initialdiagnostik, Behandlung und Verlaufserfassung des Morbus Pompe im Kindesalter.

BACKGROUND: Mechanical ventilation is used to treat respiratory failure in coronavirus disease 2019 (COVID-19). PURPOSE: To review multiple streams of evidence regarding the benefits and harms of ventilation techniques for coronavirus infections, including that causing COVID-19. DATA SOURCES: 21 standard, World Health Organization-specific and COVID-19-specific databases, without language restrictions, until 1 May 2020. STUDY SELECTION: Studies of any design and language comparing different oxygenation approaches in patients with coronavirus infections, including severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), or with hypoxemic respiratory failure. Animal, mechanistic, laboratory, and preclinical evidence was gathered regarding aerosol dispersion of coronavirus. Studies evaluating risk for virus transmission to health care workers from aerosol-generating procedures (AGPs) were included. DATA EXTRACTION: Independent and duplicate screening, data abstraction, and risk-of-bias assessment (GRADE for certainty of evidence and AMSTAR 2 for included systematic reviews). DATA SYNTHESIS: 123 studies were eligible (45 on COVID-19, 70 on SARS, 8 on MERS), but only 5 studies (1 on COVID-19, 3 on SARS, 1 on MERS) adjusted for important confounders. A study in hospitalized patients with COVID-19 reported slightly higher mortality with noninvasive ventilation (NIV) than with invasive mechanical ventilation (IMV), but 2 opposing studies, 1 in patients with MERS and 1 in patients with SARS, suggest a reduction in mortality with NIV (very-low-certainty evidence). Two studies in patients with SARS report a reduction in mortality with NIV compared with no mechanical ventilation (low-certainty evidence). Two systematic reviews suggest a large reduction in mortality with NIV compared with conventional oxygen therapy. Other included studies suggest increased odds of transmission from AGPs. LIMITATION: Direct studies in COVID-19 are limited and poorly reported. CONCLUSION: Indirect and low-certainty evidence suggests that use of NIV, similar to IMV, probably reduces mortality but may increase the risk for transmission of COVID-19 to health care workers. PRIMARY FUNDING SOURCE: World Health Organization. (PROSPERO: CRD42020178187).

The aim of this study was to examine motor performance and trainability in youths with cystic fibrosis (CF).Twenty-two children and adolescents (11 f/11 m), age range 6-17 years (11.3 ± 3.3 years), mean FEV1 91.0 ± 21.7% pred.finished the partially monitored 12-months exercise program. Patients performed the Deutsche Motorik Test (DMT) to assess flexibility, balance, strength, power and totalmotor performance. An incremental ergometer cycle test was used to assess maximal exercise capacity (Wpeak). All tests were performed before (T1), after 6 months of monitored exercise training (T3) and another 6 months without monitoring (T4).Motor Competence in total and test-items of the DMT (except foreward bend) improved to T3 (p .05). No further improvement could be observed after the end of the monitoring (T3). However, the values remained stable at the improved level (T4). Girls scored lower in test items depending on strength/power but scored higher in balancing compared to boys (p .05). Wpeak and FEV1 were not influenced by the training program. From T3 to T4 a slight decrease was observed (p ≤ .05).The findings demonstrate benefits of an individualizedmonitored long-term exercise intervention on motor performance in CF with improvements of test-tasks to predicted normal. Monitoringseems to be a facilitator in maintaining motivation toward physical activity as no further increase in motor performance was observed after stopping supervision. The results suggest that an individually tailored monitoredregular exercise program should include all aspects of physical fitness with a variety of movement experiences.

Background In patients with severe neurological impairment, recurrent respiratory tract infections frequently occur as a result of impaired clearance of airway secretions and microbial airway colonisation. We hypothesised that inhaled antibiotic therapy may improve the morbidity of these patients. Methods A retrospective data analysis of 20 patients (11 nontracheotomised and nine tracheotomised) with neurological impairment and microbial airway colonisation was carried out at a children's university hospital. Two questionnaires that asked about the number of respiratory tract infections, antibiotic therapies and hospitalisations were distributed to the patients/caregivers: a first questionnaire representing the 12 months prior to the initiation of inhaled antibiotics and a second questionnaire describing the first 12 months under therapy. Results During the first 12 months of therapy, the frequency of respiratory tract infections among all participants was reduced from a mean of 6.8 episodes (median (interquartile range (IQR)) 6.0 (4.0–10.0) episodes) to a mean of 2.5 episodes (median (IQR) 2.0 (1.0–3.0) episodes; p, Inhaled antibiotic therapy offers a novel approach to the prevention of respiratory tract infections in patients with severe neurological impairment who have chronic microbial airway colonisation and recurrent respiratory tract infections http://bit.ly/2HQRyz0

We report the case of a 19-years-old patient who presented with a perplexing variety of symptoms which included remarkable facial features, intellectual disability, granulomatous upper lip swelling (previously diagnosed as Melkersson–Rosenthal syndrome), Crohn’s-like disease, non-productive cough, and a granulomatous mass localized in the left lung. Chronic granulomatous disease (CGD) was diagnosed using dihydrorhodamine 123 assay that showed low levels of phagocytic NADPH-oxidase. DNA sequencing revealed a heterozygous mutation in the NCF-1 gene on chromosome 7. As remarkable facial features and psychomotor retardation are not associated with CGD, a more detailed genetic work-up using fluorescence in situ hybridization was performed. A microdeletion in 7q11.23 on one allele indicated Williams–Beuren syndrome (WBS). The NCF-1 gene and its two pseudogenes are part of a highly repetitive region within 7q11.23 and are prone to recombination events and deletions. Such deletions can involve both the WBS critical region and the NCF-1 wildtype gene, as was the case for our patient. The second allele of the NCF-1 gene was affected by the frequent c.75.76delGT mutation that stems from a recombination of the NCF-1 wildtype gene with one of its pseudogenes. In conclusion, patients with NCF-1-deficient CGD may also harbor microdeletions that result in WBS or other hereditary disorders; therefore, it is important to perform a thorough genetic analysis in order to initiate appropriate therapy for these patients. CA Soukup

Introduction. Antibiotic treatment regimens againstPseudomonas aeruginosalung infection in cystic fibrosis (CF) patients often include aminoglycoside antibiotics that may cause chronic renal failure after repeated courses. Aminoaciduria is an early marker of acute aminoglycoside-induced renal tubular dysfunction. We hypothesized that urinary amino acid reabsorption is decreased after repeated once-daily tobramycin therapies.Methods. In this prospective cross-sectional study creatinine clearance was estimated by the Schwartz and the Cockcroft-Gault formula. Tubular amino acid reabsorption was determined by ion exchange chromatography in 46 patients with CF who received multiple tobramycin courses (6.3±10.1(1–57)) in a once-daily dosing regimen and 10 who did not.Results. Estimated creatinine clearance employing the Cockcroft-Gault was mildly reduced in 17/46 (37%) of the patients who received tobramycin and 5/10 (50%) of the patients who did not but in none using the Schwartz formula. No association with lifetime tobramycin courses was found. Tubular amino acid reabsorption was not influenced by the amount of once-daily tobramycin courses.Conclusion. Clinically not significant reduction of eCCL occurred in a minority of CF patients. However, chronic tubular dysfunction was not present in patients with CF repeatedly treated with tobramycin in the once-daily dosing scheme.

Background In pediatric neuromuscular disorders (NMD), respiratory muscle weakness parallels respiratory failure. The objectives of this study are (1) to evaluate respiratory muscle capacity in neuromuscular children and (2) to assess the relationship between vital capacity, respiratory muscle performance, and alveolar ventilation during sleep and wakefulness. Methods Inspiratory vital capacity (IVC), peak inspiratory pressure (PIP), mouth occlusion pressure (P 0.1 ), and noninvasive tension-time index of the respiratory muscles (TTImus) were studied in 80 NMD subjects (12.1 ± 3.3 years) and 80 healthy children (11.1 ± 2.2 years). Subjects' results were compared with arterial blood gases and polysomnography. Results In 15 NMD subjects with normal ventilation IVC and PIP were reduced to 70% predicted but TTImus was normal. In 50 NMD subjects with nocturnal hypoventilation IVC and PIP were lower than 50% predicted, TTImus was doubled compared with the control group. In 15 NMD subjects with diurnal and nocturnal hypoventilation IVC and PIP were below 30% predicted, TTImus was increased fourfold, and thus the main determinant of respiratory failure. Conclusions In NMD children, reduced IVC and PIP result in increased respiratory muscle load and disturbed ventilation. TTImus is an important noninvasive determinant of disturbed ventilation in children with NMD.

Advanced stages of Duchenne muscular dystrophy (DMD) result in severe lung volume decline and are associated with high respiratory morbidity and mortality. The aim of this study was to investigate whether lung volume decline in subjects with DMD is associated with ventilation inhomogeneity measured with the multiple-breath washout technique.This cross-sectional study of lung function included 45 subjects with DMD and 16 healthy controls using multiple-breath washout, spirometry, and cough peak flow.Subjects with DMD exhibited an elevated lung clearance index (> 7.0) defined as the cumulative exhaled volume divided by the functional residual capacity to lower the sulfur hexafluoride concentration below 2.5% compared with controls (8.16 ± 2.55 vs 6.23 ± 0.46, P < .001). Lung clearance index elevation was negatively correlated with vital capacity (% predicted: r = -0.79, P < .001) and cough peak flow (L/min: r = -0.41, P = .005). Furthermore, dead-space ventilation (dead-space-to-tidal-volume ratio) and functional residual capacity showed a positive correlation with lung clearance index elevation (r = 0.81 and 0.48, P < .001). An FVC of < 24% predicted lung clearance index elevation with a sensitivity of 96% and a specificity of 80%.Moderate-to-severe lung volume decline in subjects with DMD is associated with ventilation inhomogeneity. Lung clearance index elevation may be the result of altered ventilation geometry or retention of airway secretions in the infection-free DMD subject. OA embargo

To prospectively investigate the prevalence of hepatopulmonary syndrome (HPS), the importance of pulse oximetry in diagnosing HPS, and the longitudinal course after liver transplantation in children with cirrhosis referred for liver transplantation.Fifty-six patients aged 1-17 years (mean age, 4.6 ± 5.0 years) with liver cirrhosis were screened for HPS by hyperemic capillary blood gas (CBG) analysis and contrast-enhanced transthoracic echocardiography. Eleven patients were excluded owing to conditions that can produce cardiopulmonary dysfunction, including 5 with cystic fibrosis, 1 with pulmonary arterial hypertension, and 5 with an intracardial shunt. HPS was classified in accordance with the European Respiratory Society Task Force criteria on pulmonary-hepatic disorders. Patient groups were compared for biochemical and clinical characteristics.Eighteen children (40%) with cirrhosis were intrapulmonary vasodilatation (IPVD)-positive and had a pulse oximetry oxygen saturation level98%. Two of these patients (11%) exhibited moderate HPS with an elevated alveolar arterial oxygen gradient15 mm Hg and PaO270 mm Hg; they died before undergoing liver transplantation. The sensitivity and specificity of CBG analysis for detecting elevated alveolar arterial oxygen gradient in children with IPVD was 94% and 53%, respectively. HPS was associated with late hepatoportoenterostomy (P.04). Liver transplantation led to resolution of HPS in all patients.IPVD is frequent in children with liver cirrhosis (40%). Pulse oximetry is insufficient for timely HPS diagnosis. Pathological CBG analysis data indicate IPVD in the majority of cases, but are imprecise in children aged2 years. Contrast-enhanced transthoracic echocardiography and CBG analysis are recommended for evaluation of HPS in children with cirrhosis, regardless of liver synthesis capacity and clinical chemistry data.

Retrospective data suggest that approximately half of patients with primary ciliary dyskinesia (PCD) have symptoms of neonatal respiratory distress. Respiratory distress syndrome in a full term infant should therefore raise PCD as a potential underlying disease.1,2 The non-invasive measurement of nasal nitric oxide (NO) is of diagnostic value in adults and children with PCD,1,3 but similar information is not available for neonates with PCD. A 3550 g male infant was delivered after uncomplicated …